PROJECT SUMMARY Speaking is one of the most complex actions that we perform, yet nearly all of us learn do it effortlessly. The ability to communicate through speech is often described as the unique and defining trait of human behavior. Despite its importance, the basic neural mechanisms that govern our ability to speak fluently remain unresolved. This proposal addresses two fundamental questions at the crossroads of linguistics, systems neuroscience, and biomedical engineering: 1) How are the kinematic and acoustic targets of articulation represented in human speech motor cortex?, 2) What are the coordinated patterns of cortical activation that gives rise to fluent, continuous speech?, and 3) How does prefrontal cortex govern the cognitive inhibitory control of speech (e.g. stopping)? Our studies should greatly advance understanding of how the speech motor cortex encodes the precise control of articulation during speech production as well as determine whether this control system can be harnessed for novel rehabilitative strategies. Three potential areas of impact are: Neurobiology of Language, where results will shed light on neurophysiologic mechanisms of speech motor control; Human Neurophysiology, where insight gained may suggest novel methods for machine learning-based analyses of distributed population neural activity; and Translational NeuroEngineering, where utilization of novel cortical recording technologies at unparalleled spatiotemporal resolution and duration. We propose to investigate the functional organization of the speech motor cortex during controlled vowel and syllable productions, but also from natural, continuous speech. Our methods utilizing safe, high-density, large-scale intracranial electrode recordings in humans represent a significant advancement over current noninvasive neuroimaging approaches. To accomplish this, we must innovate new, integrative approaches to speech motor control research. We have assembled a team with significant multi- disciplinary strengths in neurosurgery, neurology, ethics, computational modeling, machine learning, neuroscience, engineering, and linguistics. The most debilitating aspect of profound paralysis due to trauma, stroke, or disease is loss of the ability to speak, which leads to profound social isolation. Our research leverages foundational knowledge gained during research piloted under a NIH New Innovator (DP2) award. We wish to broaden the impact of our research in the neurobiology of speech motor control.